The rise of antimicrobial resistance (AMR) worldwide and the increasing spread of multi-drug-resistant organisms expressing metallo-β-lactamases (MBL) require the development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against Pseudomonas aeruginosa and Klebsiella pneumoniae expressing carbapenemases Verona integron-encoded metallo-β-lactamase (VIM-2) and New Delhi metallo-β-lactamase 1 (NDM-1), respectively. These adjuvants were prepared via standard chemical methods and evaluated in biological assays for potentiation of MEM against bacteria and toxicity (IC) against HepG2 human liver carcinoma cells. One of the best compounds, 15, lowered the minimum inhibitory concentration (MIC) of MEM by a factor of 32-256 at 50 μM within all tested MBL-expressing clinical isolates and showed no activity toward serine carbapenemase expressing isolates. Biochemical assays with purified VIM-2 and NDM-1 and 15 resulted in inhibition kinetics with k/ K of 12.5 min mM and 0.500 min mM, respectively. The resistance frequency of 15 at 50 μM was in the range of 10 to 10. 15 showed good tolerance in HepG2 cells with an IC well above 100 μM, and an in vivo study in mice showed no acute toxic effects even at a dose of 128 mg/kg.
Antimicrobial resistance (AMR), and in particular antibacterial resistance, is an increasingly serious threat to global public health. AMR develops when a microorganism (bacteria, fungus, virus or parasites) no longer responds to a drug to which it was originally sensitive. [1][2] Antibiotics have an enormous impact on modern medicine. They are essential in the treatment of many human diseases such as urinary tract infections, wound infections, bloodstream infections, pneumonia, tuberculosis and they are a prerequisite for chemotherapy or surgery. Without harmonized and immediate worldwide action to develop agents countering highly resistant bacteria (e.g. Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus), the world is heading towards a post-antibiotic era in which common infections could once again become life threatening. [1][2] The increase in mortality with bloodstream infections caused by methicillin-resistant S. aureus (MRSA) and third-generation cephalosporin-resistant E. coli is significant, and the prolongation of hospital stay imposes a considerable burden on health care systems. [3][4] The introduction of more potent alternatives of existing antibiotics provides only temporary
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.